Some viruses, especially HIV, must undergo a complex process called fusion in order to enter the host cell and reproduce. During fusion, the outer membrane of the virus fuses with the membrane of the host cell. In the case of HIV, the outer membrane of the HIV virus fuses with the membrane of the CD4+ T cell during reproduction.
T1249 is a member of a new class of antiviral agents that inhibit virus/membrane fusion. In the case of HIV, this provides two salutary effects:
the reproduction of HIV is blocked and resultant death of the CD4+ T cells does not occur.
Viral resistance to currently approved anti-HIV drugs is a significant issue in the clinical management of HIV today. Many patients who begin combination antiretroviral treatment with currently approved medications will develop resistance to one or more of these agents over time. Research suggests, however, that T1249 may be unaffected by resistance to any of the currently approved antiretroviral classes. (Data presented at the 5th International Workshop on Drug Resistance and Treatment Strategies in Scottsdale, Ariz., Jun. 4–8, 2001).
An analysis of T1249 dose-ranging in a clinical trial suggests that daily dose of T1249, and not prior antiretroviral treatment experience, including mutations to all approved classes of HIV drugs, is the only variable that is associated with the viral load reduction among treatment-experienced, patients. Additional experiments show that the in vitro activity of T1249 is not affected by mutations associated with resistance to reverse transcriptase inhibitors and protease inhibitors.
Like many polypeptide therapeutic agents, T1249 is generally administered by injection. Current therapeutic protocols often involve more than one daily injection.
It would, therefore, be advantageous to provide T1249 polypeptides and pharmaceutical compositions having improved performance and pharmacokinetic characteristics. It would be particularly advantageous to provide for lower therapeutic doses of T1249, less frequent administrations, and/or extended duration of action.
These and other objects of the present invention are described in greater detail below.